Herpes simplex type 1 (HSV-1) is a source of frequent infection in humans with varying degree of severity from mild discomfort (recurrent HSV labialis) to serious ocular infection including impairment of vision (Herpes keratitis) and life-threatening disease (Herpes encephalitis). Ten to fifteen percent of the population on the North American continent over the age of 18 years have recurrent Herpes infections three or more times every year (Maugh, 1976). (References appear at the end of the disclosure)
A wide variety of drugs has been tested for antiviral activity against Herpes viruses and few have been licensed for use in humans (for reviews see Corey et al., 1983; Corey and Spears, 1986; DeClercq, 1982; Hirsch and Schooley, 1983; Whitley et al., 1986). The most significant developments in the last ten years have been the discovery of drugs which elicit antiviral activity by selectively utilizing or inhibiting virus specified functions to a greater degree than host cells (Babiuk et al., 1975; DeClercq et al., 1979; Elion et al., 1977; Gupta, 1979, 1981; Helgstrand et al., 1978; and Lopez et al., 1980). This new generation of antiviral drugs includes compounds such as acyclovir, 5-bromovinyl-2'-deoxyuridine (BVdUrd), 5-ethyl-2'-deoxyuridine (EtdUrd), 5-methoxymethyl-2'-deoxyuridine and 5-iodo-2-fluoroaracytosine. The selectivity of these compounds is primarily due to specific interaction with two virus-induced enzymes, deoxythymidine-deoxycytidine (dThd/dCyd) kinase and DNA polymerase.
There are many patents and published patent applications relating to antiviral nucleosides. For instance, U.S. Pat. Nos. 4,808,614 and 4,692,434 (Hertel) relate to various 2'-deoxy-2',2'-difluoro nucleosides and their use as antiviral agents, particularly their use against Herpes simplex virus, type I.
U.S. Pat. No. 4,788,181 (Driscoll et al) relates to 2',3'-dideoxy-5-azcytidine and 5-methyl-, 5-bromo- and 5-fluoro-2',3'-dideoxycytidine and their phosphorylated derivatives for use against RNA viruses and DNA viruses, particularly Human Immunodeficiency Virus.
U.S. Pat. No. 4,382,925 (DeClercq et al) relates to the compounds E-5-(2-bromovinyl)-2'-deoxycytidine and E-5-(2-iodovinyl)-2'-deoxycytidine and their antiviral activity which is said to be very specific towards Herpes simplex virus.
PCT Application No. W087/04929 (Greer et al) is directed to the use of 5-substituted-2'-deoxycytidine in the treatment or prevention of retroviral diseases, particularly AIDS. The substituent at the 5-position is fluorine or chlorine or a methyl or trifluoromethyl group.
U.S. Pat. No. 4,210,638 (Greer) discloses pharmaceutical compositions containing 5-trifluoromethyl-2'-deoxycytidine and a cytidine deaminase inhibitor, for treating diseases caused by Herpes or Herpes-like viruses.
U.S. Pat. No. 4,230,698 (Bobek et al) is concerned with 2-substituted arabinofuranosyl nucleosides and nucleotides which are said to have useful antitumour, antiviral and antimicrobial activities. The 2-substituted arabinofuranosyl nucleosides and nucleotides are said to have been developed when searching for deaminase resistant antitumour agents.
DE No. 3002197 (Gauri) discloses 5-alkyl and 5-alkenyl substituted pyrimidine nucleosides, which can be substituted by halogen in the 5-alkyl or 5-alkenyl substituent, as virostatic and cytostatic agents.
EP No. 0216511 (Mitsuya et al) relates to the inhibition of in vitro infectivity and the cytopathic effect of HTLV-111/LAV by 2',3'-dideoxynucleosides, particularly 2',3'-dideoxycytidine and the related mono- and tri-phosphates.
PCT Application No. WO 88/09796 (Webb) is concerned with epoxide, episulphide and aziridine derivatives of nucleoside analogues and their use for the treatment or prophylaxis of retroviral infections, including AIDS.
PCT Application WO 88/00050 (Eriksson et al) discloses the use of 2',3'-dideoxy-3'-fluoro nucleosides for the control or treatment of retrovirus and hepatitis B infections.
EP 0217580 (Rideout et al) is concerned with certain novel 3'-azidonucleosides and their use in therapy, particularly the treatment and prophylaxis of gram negative bacterial infections and retroviral infections such as AIDS.
EP No. 0206497 (Koszalka et al) discloses certain 2',3'-dideoxynucleosides and their use in treatment and prophylaxis of viral, especially retroviral infections.
EP No. 0294113 (Kremitsky et al) discloses derivatives of 2',3'-dideoxycytidine in which the N4-position of the dideoxycytidine is substituted by an acyl group and/or the 5'-O-position is substituted by a C.sub.3-5 alkanoyl group. These compounds are said to be useful for the treatment or prophylaxis of viral infections, particularly retroviral infections and especially AIDS, and to show improved bioavailability over 2',3'-didoexycytidine.
EP No. 0311100 (Partridge et al) is concerned with derivatives of 2',3'-dideoxycytidine and 2'3'-didehydro-2',3'-dideoxycytidine and their use against retroviral infections, especially AIDS.
EP No. 0307914 (Soo) is concerned with 2',3'-dideoxy analogues of adenosine, thymidine, cytidine, guanosine, uridine or inosine which are said to be effective in preventing AIDS in extremely low dosages at which they exhibit no neuropathic effects.
EP No. 0254268 (Matthes et al) discloses certain 3'-deoxy-3'-fluoro nucleosides, including some which are substituted at the 5-position of the cytidine moiety, and their use to combat AIDS.
EP No. 0284405 (Frost) discloses phosphate bridged dimers of nucleoside derivatives for use as antiviral agents.
EP No. 0286413 (Weinstein) discloses the administration of phosphorylated nucleosides encapsulated in liposomes in the prevention or treatment of diseases caused by retroviruses, particularly AIDS.
EP No. 0310673 (Ueda et al) discloses novel 2'-alkylidenepyrimidine nucleoside derivatives and their use as antiviral agents.
In spite of the recent advances there is a definite need of new drugs to treat HSV-associated diseases for the following reasons:
(i) there is no drug approved for the treatment of Herpes labialis; PA1 (ii) there is a definite need of better drugs for the treatment of Herpes encephalitis; PA1 (iii) deoxyuridine analogues (BVdUrd and EtdUrd) are metabolically unstable, and poorly cross the blood brain barrier. Thus, these compounds are of limited usefulness in the treatment of systemic Herpes simplex infections; PA1 (iv) currently approved antiherpes drugs, such as acyclovir, arabinosyl adenine, trifluorothymidine, are not useful for the treatment of recurrent HSV infections in patients.